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Dominant optic atrophy
Orphanet Journal of Rare Diseases 2012, 7:46 doi:10.1186/1750-1172-7-46
Guy Lenaers ([email protected] )Christian P Hamel ([email protected] )
Cecile Delettre ([email protected] )Patrizia Amati-Bonneau ([email protected] )
Vincent Procaccio ([email protected] )Dominique Bonneau ([email protected] )
Pascal Reynier ([email protected] )Dan Milea ([email protected] )
ISSN 1750-1172
Article type Review
Submission date 1 August 2011
Acceptance date 15 March 2012
Publication date 9 July 2012
Article URL http://www.ojrd.com/content/7/1/46
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Dominant optic atrophy
Guy Lenaers1*
*Corresponding author
Email: [email protected]
Christian Hamel1,2
Email: [email protected]
Cécile Delettre1
Email: [email protected]
Patrizia Amati-Bonneau3,4,5
Email: [email protected]
Vincent Procaccio3,4,5
Email: [email protected]
Dominique Bonneau3,4,5
Email: [email protected]
Pascal Reynier3,4,5
Email: [email protected]
Dan Milea3,4,5,6
Email: [email protected]
1 Institut des Neurosciences de Montpellier, U1051 de l’INSERM, Université de
Montpellier I et II, BP 74103, Montpellier cedex 05 34091, France
2 CHRU Montpellier, Centre de Référence pour les Maladies Sensorielles
Génétiques, Hôpital Gui de Chauliac, Montpellier F-34295, France
3 INSERM U1083, Angers F-49000, France
4 CNRS 6214, Angers F-49000, France
5 Centre Hospitalier Universitaire, Angers F-49000, France
6Glostrup University Hospital, Copenhagen, Denmark
Abstract
Definition of the disease
Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral
degeneration of the optic nerves, causing insidious visual loss, typically starting during the
first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their
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axons forming the optic nerve, which transfer the visual information from the photoreceptors
to the lateral geniculus in the brain.
Epidemiology
The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to
1/30000 in the rest of the world.
Clinical description
DOA patients usually suffer of moderate visual loss, associated with central or paracentral
visual field deficits and color vision defects. The severity of the disease is highly variable, the
visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses
on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 15% of
DOA patients harbourextraocular multi-systemic features, including neurosensory hearing
loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral
neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts.
Aetiology
Two genes (OPA1, OPA3) encoding inner mitochondrial proteins and three loci (OPA4,
OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and
OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified
encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed,
as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect
mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and
maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy
metabolism and the control of apoptosis.
Diagnosis
Patients are usually diagnosed during their early childhood, because of bilateral, mild,
otherwise unexplained visual loss related to optic discs pallor or atrophy, and typically
occurring in the context of a family history of DOA. Optical Coherence Tomography further
discloses non-specific thinning of retinal nerve fiber layer, but a normal morphology of the
photoreceptors layers. Abnormal visual evoked potentials and pattern ERG may also reflect
the dysfunction of the RGCs and their axons. Molecular diagnosis is provided by the
identification of a mutation in the OPA1 gene (75% of DOA patients) or in the OPA3 gene
(1% of patients).
Prognosis
Visual loss in DOA may progress during puberty until adulthood, with very slow subsequent
chronic progression in most of the cases. On the opposite, in DOA patients with associated
extra-ocular features, the visual loss may be more severe over time.
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Management
To date, there is no preventative or curative treatment in DOA; severely visually impaired
patients may benefit from low vision aids. Genetic counseling is commonly offered and
patients are advised to avoid alcohol and tobacco consumption, as well as the use of
medications that may interfere with mitochondrial metabolism. Gene and pharmacological
therapies for DOA are currently under investigation.
Review
Disease name/synonyms
DOA: Dominant Optic Atrophy (OMIM #165500), initially called Kjer’s Optic Atrophy, was
first described by the Danish ophthalmologist Dr. PoulKjer [1]. DOA is also called
Autosomal Dominant Optic Atrophy (ADOA), to emphasize its autosomal mode of
inheritance, in contrast with Leber Hereditary Optic Neuropathy (LHON), inherited by
mutations on the mitochondrial genome and maternal lineage.
Table 1 DOA loci and genes
Locus Chromosome Gene Mode of
inheritance
OPA1 3q28-29 OPA1 dom.
OPA2 Xp11.4-p11.21 ? X-link
OPA3 19q13.2-q13.3 OPA3 dom./ress.
OPA4 18q12.2-q12.3 ? dom.
OPA5 22q12.1-q13.1 ? dom.
OPA6 8q21-q22 ? ress.
OPA7 11q14.1-q21 TMEM126A ress.
OPA8 16q21-q22 ? dom.
legend: dom: dominant; ress: recessive
Table 2 Possiblesyndroms associated to optic atrophy
Locus Optic
Atrophy
Deafness Poly
neuropathy
Multiple
Sclerosis
Myopathy
CPEO
Cardiopathy Cataract
OPA1 + +/- +\- +\- +\- - -
OPA2 + - - - - - -
OPA3 + - +\- - - - +
OPA4 + - - - - - -
OPA5 + - - - - - -
OPA6 + - - - - - -
OPA7 + +\- - - - +\- -
OPA8 + +\- - - - +\- -
legend: (+): systematic; (+/-): possible; (-): never reported
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DOAD-DOAplus: Dominant Optic Atrophy and Deafness and DOAplus (both OMIM
#125250) are syndromic forms of DOA associating neurosensory deafness (DOAD) or other
syndroms (DOAplus) like myopathy, progressive external ophthalmoplegia, peripheral
neuropathy, stroke, multiple sclerosis or spastic paraplegia.
DOAC: Dominant Optic Atrophy and Cataract (OMIM #606580) is a rare form of DOA
associated to cataract.
Orphanet reference numbers are ORPHA98673 for DOA, and ORPHA1215 for DOAplus.
Definition
DOA is an optic neuropathy due to the degeneration of optic nerve fibers. It belongs to the
group of inherited optic neuropathies (ION), which are genetic conditions affecting the retinal
ganglion cells (RGCs) whose axons form the optic nerve. Because RGCs are neurons
originating from an extension of the diencephalon, DOA is a disease of the central nervous
system [2].
DOA is a mitochondriopathy, as the genes responsible for DOA encode proteins ubiquitously
expressed, imported into the mitochondria and associated to the inner membrane [3]. As such,
DOA may be syndromic and include extra-ocular symptoms, mostly neuro-muscular, that are
frequently found in mitochondriopathies [4].
Epidemiology
DOA is a relatively common form of inherited optic neuropathy. Its prevalence is 3/100,000
in most populations in the world, but can reach 1/10,000 in Denmark where a founder effect
was identified [5,6]. DOA penetrance is around 70%, but depending on families, mutations
and study criteria [6,7], it can vary from 100% [5] to 43% [8]. Syndromic DOAD and
DOAplus account for some 15% of all DOA cases and are fully penetrant [9].
Clinical description
The disease was first described at the end of the 19th
century [10,11]. Large families were
then reported in UK [12], USA [13] and France [14], but it was after the Danish
ophthalmologist Kjer reporting 19 DOA families that this clinical entity was recognized and
assigned his name [1].
Non syndromic dominant optic atrophy
In most cases, DOA presents as a non syndromic, isolated, bilateral optic neuropathy.
Although DOA is usually diagnosed in school-aged children complaining of reading
problems, the condition can manifest later, during adult life [15-17]. DOA patients typically
experience a slowly progressive, insidious decrease of vision, which can rarely be
asymmetric, although rapid decline has also been reported in adults [18,19]. The visual
impairment is irreversible, usually moderate (6/10 to 2/10) and highly variable between and
within families. However, extreme severity (legal blindness) or very mild presentation
(subclinical decrease in visual acuity) can be encountered [20,21].
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On fundus examination, the optic disk typically presents a bilateral and symmetrical pallor of
its temporal side, witnessing the loss of RGC fibers entering the optic nerve (Figure 1A). The
optic nerve rim is atrophic and a temporal grey crescent is often present. Optic disc
excavation is not unusual, but its clinical features vary in most of the cases from that of
glaucoma. Optical Coherence Tomography (OCT) discoses the reduction of the thickness of
the peripapillary retinal nerve fiber layer in all four quadrants, but does not disclose alteration
of other retinal layers [22,23] (Figure 1B). The central visual field typically shows a
caecocentralscotoma, and less frequently a central or paracentralscotoma, while peripheral
visual field remains normal (Figure 1C). Importantly, there is a specific tritanopia, i.e. a blue-
yellow axis of color confusion, which, when found, is strongly indicative of Kjer disease
[24,25] (Figure 1D). However, in severe cases or in patients with congenital dyschromatopsia
(daltonism), interpretation of the color vision defect may be more difficult. The pupillary
reflex and circadian rhythms are not affected, suggesting that the melanopsin RGC are spared
during the course of the disease [26,27].
Figure 1 Ophthalmological description of a DOA patient. Results from ophthalmological
examination of a paradigm Dominant Optic Atrophy patient with the c.2708delTTAG
mutation in OPA1 (Right) compared to a control patient (Left). (A): Eye fundus examination
showing the pallor of the optic nerve in the DOA patient, in particular on the temporal side,
whereas the rest of the retina appears totally unaffected. (B): Optical Coherence Tomography
results emphasizing the thickness of RGC fibers (black line) at the emergence of the papilla,
which becomes abnormal in most quadrants, in particular on the temporal side, as the
measurement is included in the orange part of the diagram, whereas in the control it is
included in the green normal part. (C): Visual field examination reporting the caeco-central
scotoma in the DOA patient, whereas only the blind spot is detected in control patient. (D):
Results from a desaturated 15-Hue test presenting the pathognomonic tritanopia (blue-yellow
axis) dyschromatopsia defect in the DOA patient
Some patients harboring the pathogenic OPA1 mutation can be asymptomatic; at the opposite
end of the clinical variability spectrum, mutations of the OPA1 gene have been reported to
enhance multisystemic deficits while sparing totally the optic nerve.
Anterior and/or posterior blue-dot cerulean cataract occurs in the rare DOA patients with an
OPA3 mutation [28].
Although typical DOA is associated with a progressive and irreversible loss of vision, we
reported the case of a young man (23 years) who developed an isolated, progressive, painless
bilateral optic neuropathy as a result of central scotomas that spontaneously recovered partial
vision six months later. The patient harbored a novel heterozygous mutation in OPA1 exon
5b (c.740G > A) which was the first mutation to be described in one of the three alternative
OPA1 exons [29]. In addition, we identified another original case presenting a late onset (62
years) sequencial and acute loss of vision, associated to a novel dominant mutation
(c.2794C > T) in OPA1 [30], suggesting that alternative natural histories of DOA can be
related to OPA1 mutations.
Syndromic dominant optic atrophy
Syndromic DOAD and DOAplus patients experience full penetrance and usually more severe
visual deficits [9,31,32].
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DOAD and DOAplus with extra-ophthalmological abnormalities represent up to 15% of
DOA patients with an OPA1 mutation. The most common extra-ocular sign in DOA is
sensori-neural hearing loss, but other associated findings may occur later during life
(myopathy and peripheral neuropathy), suggesting that there is a continuum of clinical
presentations ranging from a mild “pure DOA” affecting only the optic nerve, to a severe and
multisystemic presentations. Sensori-neural hearing loss associated to DOA may range from
severe and congenital to subclinical [31-36] with intra- and inter- familial variations, and
mostly segregate with the OPA1 R445H mutation. In general, auditory brain stem responses,
which reflect the integrity of the auditory pathway from the auditory nerve to the inferior
colliculus, are absent, but both ears show normal evoked oto-acoustic emissions, reflecting
the functionality of presynaptic elements and in particular that of the outer hair cells [37].
Peripheral axonal sensory and/or motor neuropathy and proximal myopathy may be
diagnosed in some DOA patients from their third decade of life onwards, as well as a
combination of cerebellar and sensory ataxia in adulthood, multiple sclerosis-like illness and
spastic paraplegia [9,16,38,39]. Progressive external ophthalmoplegia is also frequently
diagnosed in syndromicDOAplus patients [9]. One report of a Behr syndrome associating
DOA to pyramidal signs, ataxia and mental retardation was linked to an OPA1 mutation [40]
and another report describing a severe neuromuscular phenotype associated to optic atrophy
was described in two OPA1 compound heterozygote siblings [41]. Muscle biopsy from
DOAplus patient revealed features typical of mitochondrial myopathy, as approximately 5%
of all fibers were deficient in histochemical COX activity and several fibers showed evidence
of subsarcolemmal accumulation of abnormal mitochondria, a phenotype known as ragged
red fibers [9,31,32].
Etiology
Loci and genes
DOA is not genetically highly heterogeneous, in comparison with many other ophthalmologic
or neurodegenerative disorders (Table 1). The first DOA locus, OPA1, localised on 3q28 was
initially considered as unique [42,43]. But since the discovery of the OPA1 gene in 2000
[44,45], two other loci, OPA4 and OPA5, were further identified in few families (1 for OPA4
and 2 for OPA5) presenting pure DOA [46,47]. Additional loci and genes were identified as
responsible for Optic Atrophy, but either with a X-linked mode of inheritance (OPA2)
[48,49], a recessive mode of inheritance (OPA6 and OPA7) [50,51] or as syndromic recessive
or dominant forms (OPA3 and OPA8) [28,52,53]. Thus to date, OPA1 is the major gene
responsible for DOA, accounting for at least 75% of all the patients, whereas all the other
genes or loci only contribute each for less than 1% of the patient cohort [7].
Mutations in OPA genes and their consequences on the mitochondrial
physiology
Three genes have been identified to date, OPA1, OPA3 and TMEM126a (OPA7) (Table 1);
all encode mitochondrial proteins ubiquitously expressed and associated to the inner
mitochondrial membrane, due to the presence of at least one transmembrane domain in their
sequence [51,54,55]. In OPA1, 27% of the mutations are missense, 27% are splice variant,
23.5% lead to frame shift, 16.5% are nonsense and 6% are deletion or duplication [7]. Most
of them are leading to a haplo-insufficiency situation where the mutated transcript is
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degraded by mRNA decay, thus leading to a reduction of 50% in the amount of OPA1
protein. As a direct consequence, the different mutations in OPA1 are not related to the
severity of the disease, and genotype/phenotype correlations are difficult to infer [25]. In this
respect, secondary nuclear genes, but not the mitochondrial genome, are suspected to control
the severity of the disease in non-syndromic patients [56]. Conversely, few missense
mutations in the GTPase domain of OPA1 are responsible for syndromic cases with severe
dominant negative effects [9], because the mutated protein might interfere with and inhibit
the wild-type protein. Importantly, sporadic cases, cases with de novo mutation and cases
with unknown familial history, account together for 50% of all patients. Concerning OPA3,
indirect evidences suggest that the 2 mutations so far reported in DOAC affect the trans-
membrane domain, are fully penetrant and act in a dominant negative manner, as
heterozygous carriers of a recessive mutation leading to the inhibition of OPA3 expression
are asymptomatic [52]. In the case of TMEM126a, the consanguineous recessive disease is
associated to a mutation introducing a stop codon at position 55, thus deleting 140 out of the
195 amino-acids composing the protein [51].
Analysis of OPA functions in common cell lines (HeLa, COS) and dysfunctions in patient
fibroblasts revealed a systematic susceptibility to apoptosis and mild to severe alteration of
the mitochondrial respiration activity, essentially associated to a reduced energetic coupling
[28,51,57-60]. In addition, the 8 OPA1 isoforms that result from alternate splicing of 3 exons
(4, 4b and 5b) have discrete functions in structuring the cristae, in mitochondrial membrane
dynamics, maintenance of the membrane potential, calcium clearance, interaction with the
respiratory chain complexes and maintenance of mitochondrial genome integrity [61-65]. As
a consequence, and as revealed by numerous patient fibroblast studies, mutations in OPA1
can have a direct although variable impact on these functions, [31,33,57-59,66], and possibly
the genetic background and aging might contribute to the mitochondrial phenotype, either in
a compensatory or in an accentuating manner.
Importantly, the OPA1 gene is the fifth identified nuclear gene responsible for generating
multiple deletions in the mitochondrial DNA, together with POLG1 (DNA polymerase γ),
PEO1 (twinkle), SLC25A4 (ANT1) and TP (thymidine phosphorylase). The presence of
multiple deletions in the mtDNA has been found in the skeletal muscle of the majority of
patients harbouring OPA1 mutations, even in those with isolated optic atrophy [67]. This
OPA1 related genomic instability is likely to play a crucial role in the pathophysiology of
DOA, taken into account its direct functional consequence on respiratory chain capacities and
may explain the convergence of clinical expressions between DOAplus syndromes and other
disorders related to mutations in mtDNA.
Optic nerve and animal models
The major concern in studying DOA pathophysiology concerns the question why RGCs are
most specifically affected by this disease, while the OPA genes are expressed in all cells of
the body. Histochemical studies revealed a peculiar distribution of mitochondria in retinal
ganglion cells. Indeed, they are accumulated in the cell bodies and in the intra-retinal
unmyelinated axons, where they form varicosities, and are conversely scarce in the
myelinated part of axons after the lamina cribosa [68-71]. These observations emphasize the
importance of mitochondrial network dynamic in order to maintain the appropriate
intracellular distribution of the mitochondria that is critical for axonal and synaptic functions,
and point to a possible pathophysiological mechanism associated to OPA1 that could
jeopardize RGC survival. Alternatively, RGCs are the only neurons of the body that are
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exposed to the day long stress of light, which generates oxidative species favoring the
apoptotic process [72]. Therefore the mitochondrial fragility conferred by OPA1 mutations,
together with the photo-oxidative stress could precipitate RGCs in premature cell death. A
third pathophysiological hypothesis involves the tremendous energetic requirements of
RGCs, as these neurons permanently fire action potentials, in addition through axons that are
not myelinated in the eye globe. As the energetic fuelling of RGCs soma is restricted in the
central part of the retina, due to the physical constraints imposed by the macula blood vessel
organization, one can hypothesize that due to the uncoupling of mitochondrial respiration in
OPA1 cells, the ATP synthesis in patient RGCs is limited and can not fulfill the physiological
energetic requirements for long term cell survival. Which of these hypotheses represents the
princeps mechanism responsible for the RGC degeneration remains unknown. Nevertheless,
in the last years, two mouse models with an Opa1 mutation have been generated and deeply
analyzed in terms of vision; both summarize DOA in that loss of RGCs is preeminent
[73,74]. Reduction of the scotopic, but not the photopic evoked potential response was found
in one mouse model [75], whereas light-adapted ERG and VEP responses revealed a
significant reduction in their amplitudes in another mouse model [76]. Histological
examinations revealed a decrease of the dentritic length of the RGC-On subpopulation in the
retina [77], and abnormal myelin structures, increase in micro-glia and autophagy were
noticed in the optic nerve [78]. In addition, some mild neuromuscular symptoms were found,
as locomotor activity was reduced and tremor observed in old animals, but no alteration of
the audition was detected [79], thus these Opa1 animals show some features of the syndromic
DOA forms.
Diagnostic methods
Anamnesis
Interviewing the index patient about the natural history of the disease if possible in the
presence of the family is mandatory to define when and in which context occurred the first
perception of visual loss or sight problems and how this perception evolved with time. It is
also required to link eventually the possible diagnosis of the index patient to symptoms
present among relatives. Special attention should be paid on sensorial or peripheral
neuropathy symptoms that would support the hypothesis of a pathophysiology related to a
mitochondrial deficit. Finding at least one affected member in two consecutive generations is
indicative of a dominant trait, or eventually of a mitochondrial maternal transmission, that
will further orientate the genetic investigations.
Ophthalmological examination
DOA is characterized by a bilateral symmetric vision loss. On funduscopic examination, the
cardinal sign consists in an optic nerve pallor usually bilateral and symmetric on the temporal
side in about 50% of patients and global in the other 50% [80], especially in old or severely
affected patients. In moderate cases, the optic nerve atrophy may not be visible. The
neuroretinal rim is often pale and sometimes associated with a temporal pigmentary grey
crescent. OCT examination discloses and quantifies the thinning of the fiber layer in the 4
cardinal directions at the optic nerve rim [23,81]. Profound papillary excavation is reported in
21% of eyes from OPA1 patients [82]. Visual fields examination typically reveals a central,
centrocecal or paracentralscotoma, which may be large in severely affected individuals, and
the sparing of the peripheral visual field [20]. Color vision defect, evaluated by the
desaturated 15-Hue test discloses often a blue-yellow loss dyschromatopsy, or tritanopia [25].
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Electrophysiological assessment
Visual evoked potentials (VEPs) are typically absent or delayed, but are not characteristic of
the disease. In subclinical or mildly affected patients, no alteration of the VEPs can be found.
Pattern electroretinogram (PERG) shows an abnormal N95:P50 ratio, with reduction in the
amplitude of the N95 waveform suggesting alterations of the ganglion cells layer [83].
Genetic investigations
The clinical diagnosis of an optic atrophy will orientate the genetic investigations. After
collecting 5ml of blood of the patient and its relatives and preparing total DNA, the analysis
of OPA1 gene will be performed on the DNA sample of the index patient by amplifying and
sequencing all the 31 coding exons and their flanking intron regions. If a mutation is
identified, its segregation in the family must be analyzed and its identity has to be compared
to the database hosted by the CHU d’Angers, France (http://lbbma.univ-
angers.fr/lbbma.php?id=9) to find out if the mutation is already recognized as pathogenic. If
not, the possible consequence of the mutation on OPA1 transcript and protein integrity should
be analyzed in silico, and by assessing the expression of the mutated allele by RT-PCR
amplification and sequencing. If no significant mutation is found in OPA1, then the presence
of a deletion in the gene can be tested with the Multiplex Ligation Probe Amplification
methodology [84-86]. Otherwise careful reconsideration of the anamnesis might orientate to
test either OPA3 gene or the full length mitochondrial genome. If results are still negative,
then when the family is large and many members are affected, genetic analysis of
chromosome markers can be performed to identify the causative locus and eventually a novel
pathogenic gene. Nevertheless, the identification of a morbid mutation greatly helps the
genetic counseling.
Syndromic cases
Patients with extra-ophthalmological symptoms should be referred to diagnostic centers or
hospitals specialized in mitochondrial disorders, in order to obtain additional examinations by
a multidisciplinary team including geneticists, neuro-ophthalmologists, neurologists,
otorhynolaryngologists.
The diagnosis of such multisystemic mitochondrial disorders often requires the study of the
functionality of the respiratory chain in order to evaluate the severity of the energetic
deficiency. A skeletal muscle biopsy is usually performed to measure the enzymatic activity
of the 5 respiratory complexes and the mitochondrial oxygraphy. In addition, it allows
anatomo-pathological examinations to check for the presence of mtDNA deletions,
cytochrome c deficient fibers and ragged red fibers. Alternatively, skin fibroblasts are also
often useful to evaluate the severity of respiratory chain dysfunction.
Differential diagnosis
The DOA differential diagnosis list includes all the causes of bilateral optic neuropathies, i.e.
compressive, inflammatory, demyelinating, ischemic, glaucomatous, toxic, and metabolic
optic neuropathies. However, an appropriate clinical and para-clinical work-up, including
neuro-imaging, biochemical studies or genetic tests, will rule out these causes in most of the
cases.
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Among those differential diagnosis, normal tension glaucoma (NTG) may present with signs
consistent with DOA, such as visual field defects, optic disc excavation; however, NTG
occurs late during the adulthood and central visual loss does not occur until late during the
course of the disease. Interestingly, certain allelic sequence variants in OPA1 have been
found to be more prevalent in NTG patients in comparison with controls, thus suggesting
some cross-talk pathophysiological mechanisms between these diseases. [87].
Other acquired optic neuropathies with similar presenting signs as DOA include the
nutritional/toxic optic neuropathies, which may have a mitochondrial dysfunction basis.
Among the toxic optic neuropathies, the most common is the tobacco-alcohol related optic
neuropathy. Other possible agents causing a toxic optic neuropathy include methylene,
ethylene glycol, cyanide, lead, and carbon monoxide. Finally, certain medications, including
ethambutol, isoniazid, disulfiram can cause a toxic optic atrophy.
Other hereditary optic neuropathies, such as Leber’s hereditary optic neuropathy, Wolfram’s
syndrome or other neuropathies associated with neurological diseases (spinocerebellar
ataxias, Friedreich’s syndrome, Charcot Marie-Tooth type 2A, Deafness-Dystonia-Optic
Neuropathy syndromes etc.) may, at times, present with similar signs as DOA, though the
general context and the neurological signs help to differentiate those entities.
Differential diagnosis associated to the OPA loci (table 2)
OPA2: Two families mapping on the OPA2 locus Xp11.4-p11.21 were identified [48], both
presented optic atrophy from early childhood [49], and one associated in some instances optic
atrophy to mental retardation and neurological symptoms as jerks, dysarthria,
dysdiadochokinesia, tremor and gait [88,89]. In both families, only male are affected and
female carriers showed no abnormalities.
OPA3: Patients presenting dominant mutation in OPA3 gene display an early optic atrophy
followed by a later anterior and/or posterior cortical cataract and dyschromatopsy without
systematic axis. In some cases, patients present tremor, extrapyramidal rigidity, pescavus and
absence of deep tendon reflex [28]. Patients with OPA3 recessive mutations present the
syndromicCosteff syndrome (see next paragraph).
OPA4 and OPA5: three families linked to the OPA4 or OPA5 loci present an optic atrophy
that can not be differentiated from the phenotype observed in OPA1 patients: i.e. optic nerve
pallor, decreased visual acuity, color vision defects, impaired VEP, and normal ERG and no
extra-ocular findings [46,47].
OPA6 and OPA7: Recessive forms of optic atrophy were described linked to the OPA6 and
OPA7 loci. OPA6 patients present an early onset optic atrophy slowly progressing with a red-
green dyschromatopsia [50]. Concerning OPA7, a severe juvenile-onset optic atrophy with
central scotoma was found in a large multiplex inbred Algerian family and subsequently in
three other Maghreb families with the same mutation in the TMEM126A gene, suggesting a
founder effect. In these family, some patients presented mild auditory alterations and
hypertrophic cardiopathy [51].
OPA8: One large family with a optic atrophy undistinguishable from that related to OPA1
was recently described. In this family late-onset sensorineural hearing loss, increases of
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central conduction times at somato-sensory evoked potentials, and various cardiac
abnormalities were also described in some patients [53].
DOA differential diagnosis with other hereditary optic neuropathies
Leber Hereditary Optic Neuropathy (LHON) is the major differential diagnosis for optic
atrophy type 1 (OPA1). LHON typically presents in young adults as painless acute or
subacute visual failure, occurring sequentially in both eyes, within six months. The acute
phase begins with blurring of central vision and color desaturation. The central visual acuity
deteriorates to the level of counting fingers in up to 80% of cases, associated with a large
centrocecalscotoma. In few cases, in particular in patients with the m.14484 G > A mutation,
visual acuity may partially improve over time. Males are more commonly affected than
females and women tend to develop the disorder slightly later in life and may be more
severely affected, sometimes with associated multiple sclerosis like symptoms. Other
neurologic abnormalities, such as a postural tremor or the loss of ankle reflexes are also
found. LHON is maternally inherited by mutation in the mitochondrial genome, in most
patients (95% of cases) by one of the three mutations m.11778G > A, m.14484T > C,
m.3460G > A [90].
Differential diagnosis between syndromic DOA and other diseases
Wolfram syndrome
Mutations in the WFS1 gene are generally associated with optic atrophy as part of the
autosomal recessive Wolfram syndrome phenotype (DIDMOAD, diabetes insipidus, diabetes
mellitus, optic atrophy, deafness) [91,92] or with autosomal dominant progressive low-
frequency sensori-neural hearing loss that can be associated with DOA, with or without
impaired glucose regulation [93,94], supporting the notion that mutations in WFS1 as well as
in OPA1 may lead to optic atrophy combined with hearing impairment.
Costeff syndrome
Truncating mutations in OPA3 gene are responsible for 3-methylglutaconic aciduria type 3, a
recessive neuro-ophthalmologic syndrome consisting of early-onset bilateral optic atrophy
and later-onset spasticity, extra-pyramidal dysfunction, and cognitive deficit. Urinary
excretion of 3-methylglutaconic and 3-methylglutaric acids is increased [52,95].
Charcot-Marie-Tooth type 2A2 (CMT2A) is a peripheral distal neuropathy with optic atrophy
designated as hereditary motor and sensory neuropathy type VI (HMSN VI)[96]. HMSN VI
families display subacute onset of optic atrophy and subsequent slow recovery of visual
acuity in 60% of affected individuals. In each pedigree a dominant mutation in the gene
MFN2 coding the outer mitochondrial dynaminmitofusin 2, was identified [97]. Recently a
novel mutation in MFN2as been described in a patient with a DOAplus clinical presentation,
featuring also mtDNA deletions in the calf muscle [98].
Deafness-dystonia-optic neuronopathy syndrome (DDON) is a disease associating slowly
progressive decreased visual acuity from optic atrophy beginning about age 20 years with
neuro-sensorial hearing impairment, slowly progressive dystonia or ataxia and dementia
beginning at about age 40 years. Neurologic, visual, and neuropsychiatric symptoms vary in
Page 13
degree of severity and rate of progression [99]. As the inheritance is X-linked, males are only
affected, although females may present mild hearing impairment and focal dystonia. The
DDON syndrome is linked to mutation in TIMM8A or to a deletion at Xq22, also causing X-
linked agammaglobulinemia due to the disruption of the BTK gene located telomeric to
TIMM8A [100].
Other inherited disorders of Oxidative Phosphorylation
Mitochondrial diseases featuring a defect in the respiratory chain affect about 1/4000
individuals. They include clinical presentations with widely differing genetic origin and
phenotypic expression. Their clinical expression is mainly neuromuscular and neurosensorial,
but the major physiological systems and functions may also be affected. More than a hundred
pathogenic mutations have been described in mitochondrial DNA since 1988, and new
mutations are still regularly being reported. MtDNA mutations may be secondary to the
mutations of nuclear genes encoding the proteins that ensure the maintenance of mtDNA.
Since 1995, more than 70 nuclear genes have been involved in respiratory chain defects. The
clinical defects identified in DOAplus (deafness, peripheral neuropathy, chronic external
ophthalmoplegia, myopathy, encephalopathy, multiple sclerosis-like syndromes) are typical
of those found in multisystemic mitochondrial diseases that often themselves include optic
atrophy. Thus, facing a multisystemic mitochondrial syndrome with optic atrophy it is
important to check for OPA1 mutations, but many other mitochondrial diseases not related to
OPA1 can also display a clinical presentation similar to DOAplus, as recently evidenced by
the discovery of a singular mis-sense mutation in the MFN2 gene leading to a DOAplus
phenotype [98]. Interestingly, in a few cases, the clinical presentations of OPA1 mutations
excluded optic nerve involvement [9,101], suggesting that rare OPA1-associated diseases
may tend towards clinical phenotypes far removed from the initial description of DOA.
Genetic counseling
DOA is inherited as an autosomal dominant trait. When the causative mutation has been
identified either in OPA1 or OPA3 genes, it should be present in one of the parents except in
de novo cases, and will be transmitted with a 50% chance to the proband sibs. When the
causative mutation is not identified, genetic analysis can be performed on the family if other
members are affected, in order to localize the locus responsible for the disease. Nevertheless,
in these latter cases, results might not be straightforward and genetic counseling could remain
doubtful. Otherwise, when facing simplex proband without known gene etiology, no genetic
counseling can be provided. Importantly, in isolated cases, de novo mutations were frequently
reported in OPA1 gene, allowing consequently to provide advises for family projections. In
this respect, prenatal diagnosis for pregnancies at risk is feasible but remains complicated
when considering the incomplete penetrance and the markedly variable inter- and intra-
familial expressivity of DOA.
Antenatal diagnosis
The optimal time for determining genetic risk and sensitizing future parents to genetic testing
is obviously before pregnancy. If young adults are affected or at risk, it will be appropriate to
discuss the potential risk for their offspring and the reproductive options, as pre-implantation
genetic diagnosis is available for families in which the disease-causing mutation or locus has
been identified. Alternatively, prenatal genetic diagnosis for pregnancies at risk is possible by
Page 14
analysis of DNA extracted from fetal cells obtained by amniocentesis, again when the
disease-causing allele in the affected family member has been identified.
Prenatal testing for diseases as DOA that do not affect intellect or life span is not common, as
controversies may exist among medical professionals and within families regarding the use of
prenatal testing, particularly if the testing is being considered for the purpose of pregnancy
termination rather than early diagnosis. Although most diagnostic centers will consider the
decision about prenatal testing to be the choice of the parents, careful discussions of these
issues are mandatory.
Management including treatment
The management of DOA patient consists in regular ophthalmologic examination, including
measurement of visual acuity, color vision, visual fields and OCT. To date, no specific
treatment exists, but low-vision aids in patients with severely decreased visual acuity can be
beneficial. Avoiding tobacco and alcohol intake as well as medications (antibiotics,
antivirals) which can interfere with mitochondrial metabolism can be additional prophylactic
measures.
Cochlear implants have been shown to restore a marked improved audition in patients with
syndromic DOA with neurosensorial deafness [37].
Prognosis
In most cases, the diagnosis of DOA is established before adulthood. Subsequent visual loss
is mild, but can at times worsen acutely, while spontaneous improvement is exceptionally
rare. However, patients may develop adaptative strategies, allowing them to fixate within
intact retinal regions and thus comply with a normal familial and social life, although
insertion in the professional life might be compromised by the visual defect.
Patients with syndromic DOA will experience a more severe visual defect that often will be
followed by audition impairment, which together will affect their social communication early
in adulthood. Appearance and evolution of additional symptoms can occur later during the
third or fourth decade of life, and are believed to progress slowly.
Unresolved questions and conclusions
Although OPA1, the major gene responsible for DOA has now been discovered more than ten
years ago, much remains to be understood to explain the specificity of the disease that focus
first on the optic nerve integrity. Indeed two major challenges are unanswered: the
identification of the princeps mechanism that is affected in DOA, and deciphering why
mainly RGCs are degenerating in this disease. Answering both of these questions should
facilitate the future design of treatments.
In this respect, in absence of actual treatment, we are facing a tremendous challenge in testing
therapeutic strategies on the different available models, from cell lines to animals. It is
probably not beyond reasonable hope to think that in the next ten years, treatments will be
found to restrain the RGCs loss in DOA.
Page 15
Abbreviations
DOA, Dominant Optic Atrophy; DOAD, Dominant Optic Atrophy and Deafness; DOAplus,
syndromic Dominant Optic Atrophy; OPA, Optic Atrophy; LHON, Leber Hereditary Optic
Neuropathy; ION, Inherited Optic Neuropathy; NTG, Normal Tension Glaucoma; DDON,
Deafness Dystonia and Optic Neuropathy; DIDMOAD, Diabetes Insipidus, Diabetes
Mellitus, Optic Atrophy and Deafness; CMT2A, Charcot Marie Tooth type 2A disease;
HMSN, Hereditary Motor and Sensory Neuropathy; RGC, Retinal Ganglion Cell; VEP,
Visual Evoked Potential; PERG, Pattern ElectroRetinoGram; OCT, Optical Coherence
Tomography
Competing interests
All authors declare that they have no compelling interests
Authors’ contributions
All authors have contributed to the redaction and correction of the manuscript. All authors
read and approved the final manuscript
Acknowledgements
We are indebted to the following patient foundations: Retina France, Association Française
contre les Myopathies, Union Nationale des Aveugles et Déficients Visuels, Ouvrir Les Yeux
and the Association contre les Maladies Mitochondriales.
This work was supported by the INSERM, the CNRS, Université Montpellier I et II, France
and the University of Angers, France, and by an European E-Rare program.
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Control DOA patient
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Figure 1
